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Hormonal Manipulations in CRPC

NW Clarke

Professor of Urological Oncology

Manchester UK

C

Standard Treatment of CRPC Pre 2004 (and in 2013?)

• PSA progression • 99mTc BS negative • CT scan large lymph node component

Bicalutamide stopped

Traditional Hormonal Therapies for CRPC

Addition of Anti-androgens

Addition of anti-androgen n PSA response

≥ 50%

decline

(%)

Median

duration

(months)

Bicalutamide 150 mg/day1 52 20 NA

Bicalutamide 150 mg/day2 31 23 NA

Bicalutamide 200 mg/day3 51 14 4

Nilutamide 200 or 300 mg/day4 28 29 7

Nilutamide 150 or 300 mg/day5 14 50 11

Bicalutamide 80 mg/day or flutamide 375

mg/day6

232 36 4

1. Kucuk et al. Urology 2001;58:53–8. 2. Joyce et al. J Urol 1998;159:149–53. 3. Scher et al. J Clin Oncol 1997;15:2928–38.

4. Kassouf et al. J Urol 2003;169:1742–4. 5. Desai et al. Urology 2001;58:1016–20. 6. Suzuki et al. J Urol 2008;180:921–7.

Median

OS

(months)

15*

NA

NA

NA

NA

NM

None have been shown to significantly improve overall survival

Traditional Hormonal Therapies for CRPC

Corticosteroids / oestrogens

Kelly et al. J Clin Oncol 1995;. Kantoff J Clin Oncol 1999; Tannock . J Clin Oncol 1996. Sternberg et al. Oncology 2005

Venkitaraman et al. BJU Int 2007 Smith. Urology 1998

7. Oh et al. J Clin Oncol 2004. Dawson et al. Cancer 2000.

Corticosteroids n PSA response

≥ 50%

decline

(%)

Median duration

(months)

Hydrocortisone 40 mg/day1 30 20 4

Hydrocortisone 40 mg/day2 123 22 2

Prednisone 10 mg/day3 81 22 4

Prednisone 20 mg/day4 50 9 3

Dexamethasone (0.5 mg/day)5 102 49 7

Oestrogens

DES 1 mg/day6 21 43 NA

DES 3 mg/day7 44 24 4

Transdermal oestradiol 0.6 mg/day8 24 13 3

Median

OS

(months)

NA

12.6*

NM*

11.9*

NA

NM†

NA

NA

None have been shown to improve overall survival significantly

N=270

CV Event Rate 20%

TTP for DAiS (8.6 months) was

significantly longer DA (4.5

months p<0,001)

Lancet Oncology Vol 14 April 2013

Evolving treatment in CRPC

Hormone

therapy

PLUS supportive care

(e.g. denosumab/bisphosphonates/β-emitters)

Docetaxel

Sipuleucel-T Abiraterone

Enzalutamide

Approved for use by FDA/EMA

Approved for use by FDA

mCRPC

post-chemo

Cabazitaxel

Radium 223

Abiraterone

Positive Phase III data

mCRPC

symptomatic

pre-chemo

Chemo

mCRPC

mildly

symptomatic

disease

mCRPC

asymptomatic

disease

(failed ADT)

Hormone

sensitive

mCRPC

post-chemo

Ongoing Phase III Trials in Metastatic CRPC

mCRPC

symptomatic

pre-chemo

Cabozantinib vs.

prednisone (COMET-1)†

Cabozantinib vs.

mitoxantrone +

prednisone (COMET-2)†

Cabazitaxel vs.

Docetaxel (FIRSTANA)

Cabazitaxel 20 mg/m²

vs. 25 mg/m²

(PROSELICA)

Dasatinib vs. placebo

(+ docetaxel, both arms)

(READY*)

Enzalutamide vs.

placebo (PREVAIL)

Ipilimumab vs. placebo

PROSTVAC-V/F ±

GM-CSF vs. placebo

(PROSPECT)

Tasquinimod vs.

placebo

Ipilimumab vs. placebo

following RT

Chemo

Orteronel vs. placebo

Custirsen ± docetaxel +

prednisone (SYNERGY)

Orteronel vs. placebo

Mildly

symptomatic

mCRPC

Asymptomatic

mCRPC

(failed ADT)

Cytotoxic Chemotherapy:

Docetaxel and Cabazitaxel in CRPC

● Phase 3, randomized, open-label trial of cabazitaxel + prednisone versus mitoxantrone + prednisone in mCRPC previously treated with docetaxel

– Primary endpoint: OS

– Secondary endpoints: PSA response, PSA progression, tumour response (RECIST), pain response

de Bono JS, et al. Lancet 2010;376:1147–54.

n=755

mCRPC

progression

after Docetaxel

25 mg/m2 cabazitaxel IV

every 3 weeks + prednisone 10 mg QD

(n=378)

12 mg/m2 mitoxantrone IV

every 3 weeks + prednisone 10 mg QD

(n=377)

1:1

• Docetaxel is initiated: 8 cycles 75 mg/m2 + prednisone 5 mg bid • Response after 6 cycles: PSA 256 to 162 ng/mL, small decrease on LN

8 cycles of docetaxel 75 mg/m2

Standard Treatment of CRPC Post 2005 ( ? in 2013)

Multiple lymph nodes metastases

99mTC BS

Docetaxel

• Treatment with docetaxel is stopped after 9 cycles due to PSA progression, Grade 3 fatigue and multiple lymph node metastases

• This was followed by a more rapid PSA progression

Standard Treatment of CRPC Post 2005

Novel Androgenic Approaches in CRPC

Nucleus Cytoplasm

Transcription Nuclear

localisation

Ligand-dependent

1

Alternate

ligands

2

Ligand-independent

AR splice

variants

7

Coactivators

Corepressors

5

6

Receptor tyrosine

kinase

4 Ligand-independent

activation of AR

ACTH LH

LHRH agonists

Androstenedione

AFFIRM: A Multinational Phase 3, Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study of Oral MDV3100 in

Patients With Progressive Castration-Resistant Prostate Cancer Previously Treated With Docetaxel-Based Chemotherapy

(NCT00974311)

Docetaxel

Abiraterone

Standard Treatment of CRPC in 2013 / 2014

Docetaxel

• PSA progression • Patient asymptomatic • Hb 10.5 mg/dL from 12.5 mg/dL

Abiraterone


Docetaxel

• PSA progression • Patient is now moderately symptomatic in cervical spine

(treated by paracetamol and piroxicam) • Hb 10.5 mg/dL from 12.5 mg/dL


Abiraterone

Docetaxel

Increase cervical pain with neurological symptoms in both arms, urinary retention

Abiraterone

Enzalutamide


Docetaxel

Increase cervical pain with neurological symptoms in both arms, urinary retention

Abiraterone Enzalutamide

Enzalutamide Abiraterone


• Who gets the drugs

• Who gives the drugs ?

• What is the optimal sequencing and combination

• What about poor performance status patients

• Who pays the bill…….?

Problems and Uncertainties in CRPC

Non-metastatic PSA increasing

Metastatic

Asymptomatic

Metastatic

Symptomatic

(bone pain)

Pall

iati

on

S

urv

ival

pre

ven

tio

n

Chemotherapy

Radiotherapy

Radionuclide

What Are the Aims and Expectations

Hormones


Metastatic

Asymptomatic

Metastatic

Symptomatic

(bone pain)

Pall

iati

on

S

urv

ival

pre

ven

tio

n

Chemotherapy

Radiotherapy

Radionuclide


Hormones

Chemotherapy

Radiotherapy

Radionuclide

Hormones


Metastatic

Asymptomatic

Metastatic

Symptomatic

(bone pain)

Pall

iati

on

S

urv

ival

pre

ven

tio

n

Chemotherapy

Radiotherapy

Radionuclide


Hormones

Chemotherapy

Radiotherapy

Radionuclide

Hormones

Chemotherapy

Radiotherapy

Radionuclide

Hormones


Metastatic

Asymptomatic

Metastatic

Symptomatic

(bone pain)

Pall

iati

on

S

urv

ival

pre

ven

tio

n

Chemotherapy

?



Metastatic

Asymptomatic

Metastatic

Symptomatic

(bone pain)

Pall

iati

on

S

urv

ival

pre

ven

tio

n

?



Metastatic

Asymptomatic

Metastatic

Symptomatic

(bone pain)

Palliate symptoms

Improve survival ?

Prevent onset and complications of bone metastases ?

What Are the Aims and Expectations P

all

iati

on

S

urv

ival

pre

ven

tio

n

Older Men Have a Higher Risk of

Dying Due to PCa

Skosyrev E et al. Cancer 2012;118:3062-70

Cu

mu

lati

ve in

cid

en

ce

90+

85-89

80-84

75-79

<75

Years from prostate cancer diagnosis

Cumulative incidence of PCa-related death

Same treatment

as younger patients

Geriatric intervention

=> Standard

treatment

Geriatric intervention

=> Adapted

treatment (or

palliation)

Only palliative

treatment

Treatment Should be Adapted to

Health Status

Droz JP et al. Crit Rev Oncol Hematol 2010;73:61–91

Droz JP et al. BJU Int 2010;106:462–9

No serious co-morbidity (CIRS-G

rating: 0–2) Functionally

independent

No malnutrition 70–75 years (50%

) and 80–85 years (25%)

Uncontrolled co-morbidity

Dependent in at least one

IADL

Risk of malnutrition

Reversible through geriatric

intervention

Two or more uncontrolled co-

morbidities Dependent in one

or

more IADL Severe

malnutrition

Terminal illness

Bedridden

Major co-morbidities

Cognitive impairments

Standard

Treatment

Geriatric

Intervention

Fit

Vulnerable

Frail

Too sick

What Do We Combine in CRPC ?

● Advances in the understanding of mCRPC have led to the development of new agents with diverse mechanisms of action:

– Second-generation taxanes

– Androgen-lowering agents

– AR signalling inhibitors

– Radiopharmaceuticals

– Bone Protective Agents

– Tyrosine kinase inhibitors

– Others

Hou X, Flaig TW. Adv Urol 2012;2012;978531; Fizazi K, et al. Ann Oncol 2012;23(Suppl. 10):x264–7.

Figure 2 Overall survival HR=hazard ratio. AA=abiraterone acetate. P=prednisone.

Karim Fizazi , Howard I Scher , Arturo Molina , Christopher J Logothetis , Kim N Chi , Robert J Jones , John N St...

Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the

COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study

The Lancet Oncology null 2012 null http://dx.doi.org/10.1016/S1470-2045(12)70379-0

The Affirm Study

NEJM Sept 2012

MDV3100 Placebo

Median OS (months) 18.4 13.6

Hazard ratio 0.63

P value < 0.0001

Orteronel (TAK-700): Clinical Studies

At 24 weeks, 36 patients (64% of evaluable, 38% of intent-to-treat population) had PSA

decreases of ≥50% (PSA50)

Phase 1/2 study in metastatic CRPC: Phase 2 results ▐ Percent change from baseline in PSA at 24 weeks by patient

Agus DB, et al. ASCO 2011, Chicago, IL, USA; Abstract 4531

Bars with darker shading

marked X indicate patients who

received prior ketoconazole

Patients • 1,083 patients,

progressive,

mCRPC

• Failed 1 or 2

chemotherapy

regimens, one

of which

contained

docetaxel

Orteronel (TAK-700) Registration Study C21005: mCRPC Following Docetaxel Failure

Efficacy

Endpoints Primary:

• OS

Secondary:

• PSA response

• Pain response

• rPFS

Orteronel po BID

Prednisone po BID

Placebo po BID

Prednisone po BID

rPFS = radiographic progression-free survival

www.clinicaltrials.gov; accessed June 2011

Phase III PREVAIL Trial: Study Design

CRPC R

1:1

MDV3100 160 mg daily

Placebo

Co-primary endpoints: overall survival and progression-free survival Secondary endpoints: time to first SRE; time to start of chemotherapy

Key inclusion criteria: • No prior treatment with cytotoxic chemotherapy • Asymptomatic or mildly symptomatic Estimated primary completion date – September 2014

Clinicaltrials.gov identifier # NCT00974311

Updated Interim Analysis (55% OS)

of COU-AA-302, a Randomized Phase 3

Study of Abiraterone Acetate in Metastatic

Castration-Resistant Prostate Cancer

Patients Without Prior Chemotherapy

Dana Rathkopf,1 Matthew R Smith,2 Johann S. de Bono,3 Christopher Logothetis,4 Neal D. Shore,5

Paul de Souza,6 Karim Fizazi,7 Peter F.A. Mulders,8 Paul Mainwaring,9 John D. Hainsworth,10

Tomasz M. Beer,11 Scott North,12 Yves Fradet,13 Tom Griffin,14 Youn C. Park,15 Thian Kheoh,14

Eric J. Small,16 Howard I. Scher,1,17 Arturo Molina,14 Charles J. Ryan18 on behalf of the COU-AA-302

Investigators

Rathkopf et al. ASCO GU 2013; Abstract 5 (Oral Presentation)

Abiraterone and Time to rPFS

100

80

60

40

20

0

0

Su

bje

cts

Witho

ut P

rogre

ssio

n

or

Dea

th (

%)

6 12 18 30 36 24

546

542

389

244

240

133

157

78

20

7

0

0

Abiraterone

Prednisone

117

45

Months From Randomization

Abiraterone

Prednisone

Abiraterone (median, mos): 16.5

Prednisone (median, mos): 8.3

HR (95% CI): 0.53 (0.45-0.62)

p Value: < 0.0001

15 9 3 21 27 33

485

406

311

176

195

99

131

62

66

20

4

0


Abiraterone and Overall Survival

100

80

60

40

20

0

0

Su

bje

cts

Witho

ut D

ea

th (

%)

6 12 18 30 36 24

546

542

524

508

482

465

421

400

68

67

0

0

Abiraterone

Prednisone

333

283

Months From Randomization

Abiraterone

Prednisone

Abiraterone (median, mos): 35.3

Prednisone (median, mos): 30.1

HR (95% CI): 0.79 (0.66-0.95)

p Valuea: 0.0151

15 9 3 21 27 33

538

534

503

492

452

437

393

361

175

153

15

9


Subsequent Therapy After Abiraterone

Abiraterone (n = 419)

n (%)

Prednisone (n = 482)

n (%)

No. with selected subsequent therapy for mCRPCa 274 (65) 347 (72)

Docetaxel 239 (57) 304 (63)

Cabazitaxel 60 (14) 70 (15)

Ketoconazole 39 (9) 63 (13)

Abirateroneb 38 (9) 78 (16)

Sipuleucel-T 33 (8) 28 (6)

Rathkopf et al. ASCO GU 2013; Abstract 5

Safety Profile

Abiraterone (n = 542)

%

Prednisone (n = 540)

%

Adverse event All grades Grades 3/4 All grades Grades 3/4

Fatigue 40 2 35 2

Fluid retention 29 1 24 2

Hypokalemia 17 3 13 2

Hypertension 22 4 14 3

Hyperglycemia 9 3 8 2

Weight gain 5 0 7 0

Cardiac disorders 21 7 18 4

ALT increased 12 6 5 1

AST increased 11 3 5 1

. Rathkopf et al. ASCO GU 2013; Abstract 5

COU-AA-302

Updated Interim Analysis: Summary

8.2 months rPFS improvement (16.5 vs 8.3 months)

5.2 months OS improvement (35.3 vs 30.1 months)

9.7 months delay chemotherapy (26.5 vs 16.8 months)

Delayed time to opiate use (NR vs 23.7 months)

Improved QoL

Tolerated treatment with longer exposure




• What is the optimal sequencing and

combination




Chemotherapy or Hormonal

Treatment First ?

When Should Chemotherapy be Started?

● Not all men are suitable for chemotherapy

● Both QoL and pain can be improved by chemotherapy

● Men with minimal symptoms had prolonged survival

Berthold, D. R. et al. J Clin Oncol; 26:242-245 2008

Should Docetaxel Responders be Re-Treated

• Re-Treatments of Initial Responders

• 59% Response to 1st Line

• 90% Response to 2nd Line

• 71% Response to 3rd Line

• Duration of Response 24 + 21 Weeks

• N Sepsis 2.9 1st Line /4.2 2nd Line /5.2 % 3rd Line

Ansari et al GU ASCO 2009 # 185

TROPIC results: Efficacy

● Median follow-up: 12.8 months

● Median OS:

– Cabazitaxel 15.1 months

– Mitoxantrone 12.7 months

CI=confidence interval; HR=hazard ratio. de Bono JS, et al. Lancet 2010;376:1147–54.

0

20

40

60

80

100

0 6 12 18 24 30

Mitoxantrone (n) 377 300 188 67 11

Cabazitaxel (n) 378 321 231 90 28

Mitoxantrone

Cabazitaxel

1

4

Su

rviv

al (%

)

Months

HR=0.70 (95% CI: 0.59–0.83); p<0.0001

30% reduction in risk of death

Novel Androgen Receptor Signalling

● Should all patients receive this routinely as the first 2nd line agent

● How do we decide whether to give chemotherapy 1st or 2nd

● How will regulation affect sequencing ?

Docetaxel in Chemotherapy-naive Patients

after Abiraterone Failure

N = 35

TAX 3271

(Docetaxel q3w)

Phase I-II2

(Abiraterone →Docetaxel)

PSA decrease ≥ 50% 45% 26%

Time to PSA progression

(median) 7.7 mo 4.6 mo

Overall survival

(median) 18.9 mo 12.5 mo

1. Tannock IF et al. N Engl J Med 2004;351:1502-12

2. Mezynski J et al. Ann Oncol 2012;epub ahead of print.

Docetaxel after AA failure maybe not as effective as docetaxel 1st line

Androgen Receptor Inhibition After

Chemotherapy

COU-AA-3011

(Abiraterone vs Placebo)

AFFIRM2

(Enzalutamide vs Placebo)

OS after 1 prior line

chemotherapy 17.1 vs 11.7 mo NR vs 14.2 mo

OS after 2 prior lines

chemotherapy 14.2 vs 10.4 mo 15.9 vs 12.3 mo

1. Fizazi K et al. Lancet Oncol 2012

2. Scher H et al. N Engl J Med 2012;367:1187-97

Abiraterone and enzalutamide both effective after 2 lines of chemotherapy

Malik Z et al. J Clin Oncol 2012;30 (Suppl):abstract e15135

Abiraterone

Median OS 8 months

Cabazitaxel

Median OS 18 months

Cu

mu

lati

ve

su

rviv

al

1.

0

0.

8

0.

6

0.

4

0.

2

0

0 3 6 9 12 15 18 21

Months (Treatment start)

─ Docetaxel → Cabazitaxel

─ Docetaxel → Abiraterone

Sequence after Docetaxel Failure

100

80

60

40

20

Surv

ival (%

)

0

0 3 6 9 12 15 18 21

Time to Death (Months)

AA ECOG 0-1

15.3 months

Placebo ECOG 0-1

11.7 months

AA ECOG 2

7.3 months

Placebo ECOG 2

7 months

OS: ECOG status (0-1 vs 2)

ECOG Status

Scher et al. J Clin Oncol 2011; 25 (suppl 7); Abstract 4 (oral presentation)

Prior Chemotherapy

OS: 1 prior line of chemotherapy OS: 2 prior lines of chemotherapy

100

80

60

40

20

Su

rviv

al (%

)

0

0 3 6 9 12 15 18 21


AA

15.4 months

AA

14.0 months

Placebo

10.3 months

100

80

60

40

20 S

urv

iva

l (%

)

0 0 3 6 9 12 15 18 21


Placebo

11.5 months

de Bono et al. Ann Oncol 2010; 21 (10 suppl 8): Abstract LBA5 (oral presentation)

Scher et al. J Clin Oncol 2011; 25 (suppl 7): Abstract 4 (oral presentation)

Pain Status

OS: Pain

(0-3 [absent]) OS: Pain

(4-10 [present])

100

80

60

40

20

Su

rviv

al (%

)

0 0 3 6 9 12 15 18 21


100

80

60

40

20

Su

rviv

al (%

)

0 0 3 6 9 12 15 18 21


AA

16.2 months

Placebo

13 months

AA

12.6 months

Placebo

8.9 months

Scher et al. J Clin Oncol 2011; 25 (suppl 7); Abstract 4 (oral presentation)

*Brief Pain Inventory scale

Costs

• £2930 / Month ($4640)

• £46,800-50,000 / QALY

• Initially rejected by NICE:

“Too Costly”

• Accepted June 2012 after

“Renegotiation of the

price”

Hormonal Manipulations in CRPC

NW Clarke

Professor of Urological Oncology

Manchester UK

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